Carbalkoxyhydrazones of the androstane series



United States Patent 3,225,072 CARBALKOXYHYDRAZONES OF THE ANDROSTANE SERIES Romano Deghenghi, Westmount, Quebec, Canada, as-

signor to American Home Products Corporation, New

York, N.Y., a corporation of Delaware No Drawing. Filed July 28, 1964, Ser. No. 385,773 8 Claims. (Cl. 260-3975) The present invention relates to novel steroidal compounds. More particularly the present invention relates to androstane derivatives.

The novel compounds of the present invention, which are potent anabolic agents with low androgenicity, are represented by the following formula:

in which R is selected from the group which consists of lower alkyl groups containing from 1 to 3 carbon atoms; R is selected from the group which consists of hydrogen and methyl; and Z represents the C and D rings of the usual steroid nucleus, together with their respective substituents.

The novel compounds of the present invention are prepared by reacting a carbalkoxyhydrazine with the appropriate steroidal 3-ketone in a suitable solvent and isolating the desired 3-carbalkoxyhydrazone. A suitable solvent is glacial acetic acid, and the reaction is advantageously carried out for several hours at room temperature.

A singular feature of this invention is the presence of unexpected and surprising biological properties in the novel compounds, which possess highly favorable anabolic to androgenic ratios generally superior to those of their respective starting materials.

Anabolic agents are useful in speeding recovery after operations, in promoting nitrogen retention and the building of protein reserves, in the treatment of muscular weakness, and in combating poor appetite, cachexia or osteoporosis. They may be administered by subcutaneous or intramuscular injection, or they may be given orally. Such anabolic agents, moreover, are useful in both animals and human beings for increasing body weight.

ice

The compounds of my invention exhibit excellent separation of anabolic from androgenic activities as measured by the ratio of weights of the levator ani to ventral prostate, having ratios greater than unity. Some presently available anabolic. drugs, used in medicine, are characterized by a ratio of levator ani weight to ventral prostate weight of less than one-half, thus indicating the great superiority of the compounds of this invention.

The following examples serve to illustrate but are not intended to limit the scope of the invention.

Example 1 To a quantity of methyltestosterone (3.0 g.) in ml. glacial acetic acid there was added 3.0 g. of carbethoxyhydrazine, C H O.CO.NH.NH The mixture was kept at room temperature for 16 hours then poured into ice-water and the product collected on a filter. Crystallization from methylene chloride-hexane mixture afforded Hot-methyl- 4-androsten-17153-01-3-carbethoxyhydrazone, M.P. 168- 170.

Example 2 To a quantity of 17a-ethyl-l9-nor-18-methyl-4-androsten-17fl-ol-3-one (200 mg.) in 5 ml. acetic acid there was added 200 mg. of carbethoxyhydrazine and the mixture kept at room temperature for 22 hours. Working up as in Example 1 provided l7a-ethyl-19-nor-18-methyl- 4-androsten-17 8-ol-3-carbethoxyhydrazone as a solid compound, melting at 206-208 C.

Example 3 To 1.0 g. of 17a-methyl-9a-fiuoro-4-androsten-115,17,9- diol-3-one dissolved in methylene chloride (15 ml.) and acetic acid (20 ml.) there was added 1.0 g. of carbethoxyhydrazine. Working up as in the previous examples, followed by chromatographic purification on silica, alforded the product, 17a-methyl-9a-fluoro-4-androsten-l1 3,17}?- diol-3-carbethoxyhydrazone.

When carbomethoxyhydrazine, CH O.CO.NH.NH was substituted for carbethoxyhydrazine, the corresponding 3- carbornethoxyhydrazone was obtained.

Example 4 The following starting materials were treated with the indicated hydrazine derivative according to the previously Starting Compounds 17B-hydroxy 5a-androstan-B-one Testosterone propionate l -nortestosterone described procedures, thus furnishing the corresponding products hereinafter set forth:

Hydrazlne Derivative Products R0CONH-NH2 R=CH; l7fi-hydroxy-5a-androstan3-earbomethoxydrazone.

R=CzHu- 17B-hydroxy-5a-androstan-B-carbethoxyhydrazone.

R=C3H1 17,3-hydroxy-5a-androstan-3-carbopropoxyhydrazone.

R=C1H ZQ-methyI-UB-proplonoxy-h-androstan-B- carbethoxyhydrazone.

R=C7H5 1-rnethyl-17Bacetoxy-5a-androst-1-ene-3- carbethoxyhydrazone.

R=CHT 17a-ethyl-17B-hydr0xy19n0r-4-androstene- B-carbomethoxyhydrazone.

R=C1Hr- 4-chloro-17fl-acetoxy4-androstene-3- carbethoxyhydrazone.

R=C H 17mmethyl-4-hydroxy-et-androsten-Uflol-3-carbethoxyhydrazone.

R=CH;- 17 5-prop1onoxy-4-androsten-3-carbomethoxyhydrazone.

R=C:H 17B'pr0pionoxy-4-androsten-3-carbethoxyhydrazone.

R=C H 17B hydroxy-19-nor-4-androstene-3-earbopropoxyhydrazone.

in which R is selected from the group consisting of lower alkyl groups containing from 1 to 3 carbon atoms; R is selected from the group consisting of hydrogen and methyl; and Z represents the C and D rings of the usual steroid nucleus, together with their respective substituents, said steroid compound being selected from the group consisting of 17a-methyl-4-androsten-175-01-3-carbethoxyhydrazone, 170a ethyl-l9-nor-18-methyl-4-androsten-17B-0l-3-carbethoxyhydrazone, 17u-methy1-9a-fluoro-4-androsten-1 1p, 17fl-diol-3-carbethoxyhydrazone, 17a methyl-9a-fiuoro-4-androsten-11,8,1713-diol-3-carbomethoxyhydrazone, 17/3-hydroXy-5u-androsten-3-carbornethoxyhydrazone, 17fi-hydroXy-5a-androstan-3-carbethoxyhydrazone, 17p-hydroxy-5u-androstan-3-carbopropoxyhydrazone, 20c methyl-17fi-propionoXy-5a-androstan-3-carbethoxyhydrazone, 1 methyl-17fi-acetoxy-5a-androst-1-ene-3-carbethoxyhydrazone,

17a ethyl-17fi-hydroxy-l9-nor-4-androstene-3-carb0methoxyhydrazone, 4 chloro 17fi-acetoXy-4-androstene-3-carbethoxyhydrazone, 170a methyl-4-hydroXy-4-androsten-17/9-ol-3-carbethoxyhydrazone, 17fi-propionoXy-4-androsten-3-carbomethoxyhydrazone, l7fi-propionoxy-4-androsten-3-canbethoxyhydrazone, and 17;? hydroxy-l9-nor-4-androstene-3-carb-opropoxyhydrazone.

2, 17a methyl '4 androsten 17,8 ol 3 carbethoxyhydrazone.

3. 17a ethyl l9 nor 1'8 methyl 4 androsten- -1-7,8-ol-3-c-arbethoxyhydrazone.

4. 17a methyl 9a iluoro 4 and-rosten 115,175- diol-3-carbethoxyhydriazone.

5. 170a methyl 9a fiuoro 4 an-drosten 11,63,175- 'diol-3-carbomethoxyhydrazone.

6. 17a ethyl 17p hyd-roxy -19 nor 4 androstene- 3-carbomethoxyhydrazone.

7. 17B propionoxy 4 androstene 3 oarbomethoxy- 'hydraZ-one.

8. 175 hydroxy 19 nor 4 androstene 3 carbopropoxyhydnaZ-one.

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3,225, 072 December 21, 1965 Romano Deghenghi It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

carbomethoxyhydrazone Signed and sealed this 28th day of June 1966? (SEAL) Attest:

ERNEST W. SWIDER Attesting Officer EDWARD J. BRENNER Commissioner of Patents 

1. A STEROID COMPOUND OF THE FORMULA: 